This project will study the mechanisms by which cell damage and death are produced by certain toxic compounds. Calcium has been implicated as the mediator of cell death induced by a number of organ specific toxins. Specifically the project will determine the role of inhibition of the endoplasmic reticulum calcium pump in mechanisms of halogenated hydrocarbon hepatotoxicity. The project will involve pharmacological and toxicological studies in intact animals, isolated hepatocytes and isolated membrane fractions in vitro. By combining these approaches the project will examine a postulated mechanism by which damage to the endoplasmic retuculum calcium pump can explain the observed dependence of toxin action on extracellular calcium. The hepatotoxins to be sutdied in the proposal are known to contaminate our drinking water and certain self contained atmospheres thus and relate the project to environmental problems assiciated with human health. The long term objectives of the project would extend the studies form one class of hepatotoxins (halogenated hydrocarbons) to other chemicals and drugs that produce hepatotoxicity as an unwanted effect.